Substituted thienopyrans

ABSTRACT

Substituted thienopyrans and processes for preparing the thienopyrans are disclosed. The thienopyrans are useful as antihypertensive agents; antianginals are peripheral antivasoconstrictive agents.

This is a division of application Ser. No. 249,043, filed Sept. 23,1988, now U.S. Pat. No. 4,992,435.

FIELD OF THE INVENTION

The present invention relates to substituted thienopyran derivatives ofthe formula: ##STR1## and

R₁ and R₂ are selected from the group consisting of hydrogen, nitro,cyano, trifluoromethyl, halogen such as bromo, chloro, iodo, alkyl(C₁₋₄), acyl (C₂₋₄), substituted acyl (C₂₋₄) (wherein the substituent ishalogen such as bromo, chloro, fluoro or iodo), benzoyl, substitutedbenzoyl (wherein the substituent is halogen such as bromo, chloro, iodo,alkyl (C₁₋₄), alkoxy (C₁₋₄), acyl (C₂₋₄), nitro, cyano ortrifluoromethyl), alkoxy(C₁₋₄)carbonyl, CHO, COOH, CONH₂, CON(R)₂wherein R is alkyl (C₁₋₄), NHCOR wherein R is alkyl (C₁₋₄), alkoxy(C₁₋₄), phenyl or substituted phenyl [wherein the substituent is halogensuch as bromo, chloro, iodo, lower alkyl (C₁₋₄), lower alkoxy (C₁₋₄),nitro, cyano, trifluoromethyl or lower acyl (C₁₋₄)]

R₃ and R₄ are selected from the group consisting of hydrogen, acyl(C₂₋₅), substituted acyl wherein the substituent is CN or CF₃ loweralkyl (C₁₋₄), cycloalkyl (C₃₋₆), cycloalkyl carbonyl (C₃₋₆), pyridylcarbonyl, benzoyl, substituted benzoyl [wherein the substituent ishalogen such as bromo, chloro, iodo, lower alkyl (C₁₋₄), lower alkoxy(C₁₋₄), lower acyl (C₂₋₄), trifluoromethyl, nitro, cyano RCONH wherein Ris alkyl (C₁₋₄)] or R₃ R₄ N together may form a heterocyclic ring suchas a pyrrole, pyrrolidine or piperidine ring or a lactam having 3-6carbon atoms or a glycine anhydride;

R₅ is hydrogen or together with R₆ forms a double bond;

R₆ is hydrogen, hydroxy, alkoxy (C₁₋₆), acyloxy (C₂₋₇), benzoyl,substituted benzoyl (wherein the substituent is halogen such as bromo,chloro, iodo, lower alkyl (C₁₋₄), lower alkoxy (C₁₋₄), lower acyl(C₂₋₄), nitro, cyano or trifluoromethyl); and

R₇ and R₈ are hydrogen or alkyl (C₁₋₄) and together may form a ringhaving 5-8 carbon atoms.

The substituted thienopyran derivatives are relaxants of smooth muscletone and as such have utility in vascular tissue for the treatment ofhypertensive disease, angina and other vascular disorders characterizedby poor regional perfusion (e.g. Raynaud's disease). Other possibleutilities include bronchodilation, uterine relaxation, gut motilitydisorders, and treatment of incontinence. These compounds also areintermediates in possible utilities include bronchodilation, uterinerelaxation, but motility disorders, and treatment of incontinence. Thesecompounds also are intermediates in the preparation of agents havingsimilar pharmacological properties.

DESCRIPTION OF THE PRIOR ART

European Patent Application No. 120 426 describes substitutedbenzopyrans useful as antihypertensive agents having the followingformula: ##STR2##

European Patent Application No. 139992 describes substituted benzopyransuseful as antihypertensive agents having the following formula: ##STR3##

European Patent Application No. 205 292 describes substituted pyrano[3,2-c] pyridine derivatives useful as antihypertensive agents havingthe following formula: ##STR4##

British Patent No. 013786 describes pyrano [3,2-c] pyridine deravativesuseful as antihypertensive agents having the following formula: ##STR5##

Thiophene analogs of antiviral flavans having the following formula:##STR6## are known in the art [Arch. Pharm. (Weinheim) 318, 70 (1985)].

Thiophene isosteres of flavones and xanthones having the followingformula: ##STR7## are also known in the art [Tetrahedron, 33, 191(1977)].

DETAILED DESCRIPTION OF THE INVENTION

The invention in its broadest aspects relates to substitutedthienopyrans which are useful as antihypertensives. Several of theintermediates used to make the thienopyrans are also novel compounds andare considered to be part of the invention.

The substituted thienopyrans of this invention are prepared as outlinedin Scheme 1.

As can be seen from Scheme 1,3-methoxythiophene (1) prepared from3-bromothiophene [S. Gronowitz, Arkiv. Kemi., 1958, 12, 239], is treatedwith 3,3-disubstituted acryloyl chloride and a Lewis acid catalyst suchas tin (IV) chloride, ferric chloride, zinc chloride or the like in aninert solvent such as methylene chloride, chloroform or THF at 0°-25° C.for 1-24 h to give the unsaturated ketone derivative 2. The methoxygroup on 2 is cleaved by the action of agents such as boron trifluoride,boron tribromide, boron trichloride, pyridinium hydrochloride ortrimethylsilyl iodide in an inert solvent such as methylene chloride orchloroform at -20° to 20° C. to give the alcohol 3. Treatment of 3 withprotic acids such as p-toluenesulfonic acid in an inert solvent such asbenzene, toluene or the like at reflux temperatures gives the5,5-disubstituted thieno [3,2-b]pyran-7-one 4. Reduction of the ketone(4) by reducing agents such as sodium borohydride, lithium aluminumhydride or the like in suitable solvents such as alcohols or THF yieldsthe alcohol 5. Dehydration of 5 under acid conditions (p-toluenesulfonicacid, for example) at -20° to 20° C. with molecular sieves in an inertsolvent such as dichloromethane, THF or benzene to remove water givesthe olefin 6. Alternatively, the ketone (4) may be reduced and thecrude, unisolated alcohol (5) may be directly converted to the olefin(6) under similar conditions. Conversion of the olefin (6) to thebromohydrin (7) is accomplished by the action of N-bromosuccinimide andwater in solvents such as DMSO or DMF at 0° to 50° C. The bromohydrin(7) is used generally without isolation and treated with bases such assodium hydride or sodium hydroxide in solvents such as DMSO or DMF at-20° to 20° C. to form the unstable epoxide (8). Anions of amine oramide derivatives are prepared in situ by treating various amines suchas pyrrolidine or piperidine or amides such as pyrrolidinone,piperidinone, caprolactam, benzamide and substituted benzamides such asp-nitrobenzamide with sodium hydride in solvents such as DMF or DMSO atroom temperature. The epoxide (8) in solvents such as DMF, DMSO or thelike is then treated with the thus-formed amine or amide anions at 0° to20° C. for 1-8 days to form 9 (R₁ R₂ =H). Reaction of 9 withelectrophiles such as bromine or nitric acid or the like gives thecorresponding substituted thienopyran (9) wherein R₁ R₂ =bromine ornitro, for example. When the electrophile is an acylating agent such as,for example, acetyl chloride or acetic anhydride and the reaction iscarried out in the presence of a Lewis acid or protic acid catalyst atabout -20° to 20° C. for about 1 hour to 6 days, the product is theacyloxy derivative (10) (R₁ R₂ =H). Similar reactions with theappropriate electrophile under similar conditions produces the acylacetate (10) (R₁ or R₂ =acyl, for example, acetyl). Reaction of theacetate 10 with methanolic sodium hydroxide or sodium carbonate at about0°-25° C. for 1-24 hours yields 9 (R₁ or R₂ =acyl, for example, acetyl).

Reaction of 9 with bases such as sodium hydride in solvents such as THF,DMF or the like at 40°-150° C. for 1-16 hours produces enamine (9a).

Alternatively, epoxide 8 is reacted with sodium azide in polar solventssuch as DMF or DMSO at about -20° to 100° C. to give azide 9 (NR₃ R₄=N₃). ##STR8## Reduction of the azide with typical hydride reducingagents such as lithium aluminum hydride or sodium borohydride insolvents such as diethyl ether, tetrahydrofuran or alcohols at about 0°to 100° C. or with metals such as zinc or iron in acetic acid or dilutehydrochloric acid gives the corresponding aminoalcohol 9 (R₃, R₄ =H).Reaction of this amine with acylating agents such as acetyl chloride,benzoyl chloride or substituted benzoyl chlorides, for example, givesthe compounds of the invention 9 wherein R₃ or R₄ is an acyl group suchas acetyl, benzoyl or substituted benzoyl.

Deprotonation of 9 (R₁ R₂ =H) with an agent such as n-butyl lithium,sec-butyl lithium, t-butyl lithium, lithium diisopropylamide or the likein an inert solvent such as THF gives an anion which is reacted withDMF, carbon dioxide or an alkyl chloroformate to give 10 (R₁ R₂ =CHO,CO₂ H, CO₂ R₉ where R₉ =alkyl C₁₋₄). Reaction of 10 (R₁ R₂ =COOH) withthionyl chloride produces 10 (R₁ R₂ =COCl) which is reacted with ammoniaor amines to produce amides 10 (R₁ R₂ =CONH₂ or CONHR₉). Treatment of 10(R₁ R₂ =CONH₂) with dehydrating agents such as trifluoroacetic anhydrideproduces 10(R₁ R₂ =CN). Treatment of the acetate 10 as before with mildbases produces 9. ##STR9##

The thieno [2,3-b]pyran compounds of this invention are preparedaccording to Scheme 2. As can be seen from the reaction sequence,2-methoxythiophene (11) prepared from 2-bromothiophene [Arkiv. Kemi.,1958, 12, 239] is treated with bromine in an inert solvent such asmethylene chloride, chloroform or THF at 0° to about 25° C. for about1-24 h to give the 2,5-disubstituted thiophene (12). Compound 12 is thentreated with a 3,3-disubstituted acryloyl chloride and a Lewis acidcatalyst such as tin (IV) chloride, ferric chloride, zinc chloride orthe like in an inert solvent such as methylene chloride, chloroform orTHF at about 0° to 25° C. for about 1-24 h to give the unsaturatedketone derivative (13). The bromine is cleaved by the action of agentssuch as trialkyltin hydrides [Synthesis, 1970, 10, 499] either neat orin an inert solvent such as ether, benzene or bromobenzene to give 14 .The methoxy group is cleaved by the action of agents such as borontrifluoride, boron tribromide, boron trichloride, pyridiniumhydrochloride or trimethylsilyl iodide in an inert solvent such asmethylene chloride or chloroform at about -20° to 20° C. to give the2-hydroxy-3-substituted thiophene which is not isolated, generally, butis treated with protic acids such as p-toluenesulfonic acid in an inertsolvent such as benzene, toluene or the like at about 0° to 200° C. togive the 3,3-disubstituted thieno[2,3-b]pyran-5-one (15). Using reactionconditions essentially as described in Scheme 1, reduction of the ketone(15) by reducing agents forms alcohol 16. Dehydration of 16 gives theolefin 17. Alternatively, the ketone 15 may be reduced and the crude,unisolated alcohol 16 may be directly converted to 17 under similarconditions. Conversion of 17 to bromohydrin 18 is accomplished by theaction of N-bromosuccinimide and water in polar solvents. Thebromohydrin is generally used without isolation and treated with basesto form the unstable epoxide 19. Anions of amine or amide derivativesare prepared in situ by treating various amines such as pyrrolidine orpiperidine or amides such as pyrrolidinone, piperidinone, caprolactam,benzamide and substituted benzamides such as p-nitrobenzamide withsodium hydride. Epoxide 19 is treated with the thus-formed amine oramide anions to form 20 (R₁ R₂ =H). Reaction of 20 with electrophilessuch as bromine or nitric acid or the like gives the substitutedcompound (20) wherein R₁ R₂ =bromine or nitro, for example. When theelectrophile is an acylating agent such as acetyl chloride or aceticanhydride and the reaction is carried out in the presence of a Lewisacid or protic acid catalyst at about -20° to 20° C. for 1 hour to 6days, the product is the acyloxy derivative 21 (R₁ R₂ =H). Furtherreaction under similar conditions produces the acyl acetate 21 (R₁ or R₂=acyl, for example, acetyl). Reaction of 21 with methanolic sodiumhydroxide or sodium carbonate at about 0°-25° C. for 1-24 hours yieldsthe acyl compound (20) (R₁ or R₂ =acyl, for example, acetyl).

Deprotonation of 20 (R₁ R₂ =H) with an agent such as n-butyllithium,sec-butyl lithium, t-butyl lithium, lithium diisopropylamide or the likein an inert solvent such as THF to give an anion which is reacted withDMF, carbon dioxide or an alkyl chloroformate to give 21 (R₁ R₂ =CHO,CO₂ H, CO₂ R₉ where R₉ =alkyl C₁₋₄). Reaction of 21 (R₁ R₂ =CO₂ H) withthionyl chloride produces 21 (R₁ R₂ =COCl) which is reacted with ammoniaor amines to produce amides 21 (R₁ R₂ =CONH₂ or CONHR₉). Treatment of 21(R₁ R₂ =CONH₂) with dehydrating agents such as trifluoroacetic anhydrideproduces 21 (R₁ R₂ =CN). Treatment of the acetate 21 as before with mildbases produces 20.

Alternatively, in a manner analogous to scheme 1, epoxide 19 is reactedwith sodium azide to give azide 20 (NR₃ R₄ =N₃). Reduction of the azidegives the aminoalcohol 20 (R₃, R₄ =H). Reaction of this amine withacylating agents such as acetyl chloride, benzoyl chloride orsubstituted benzoyl chlorides, for example, gives the compounds of theinvention (20) wherein R₃ or R₄ is an acyl group such as acetyl, benzoylor substituted benzoyl.

The thieno[3,4-b]pyrans are prepared according to Scheme 3. In thisreaction sequence, 3,4-dibromothiophene is converted by literatureprocedures [Tetrahedron, 1965, 21, 3331] to 3-bromo-4-t-butoxythiophene(22) which in turn is converted to 3-lithio-4-t-butoxythiopheneaccording to the same literature procedure. Reaction of the 3-lithiocompound with a 3,3-disubstituted acryloyl acid derivative such as themethyl or ethyl ester, acid chloride, anhydride or amide derivatives atabout -70° to 50° C. gives the unsaturated ketone derivative (23).Reaction of 23 with protic acid catalysts such as p-toluenesulfonicacid, sulfuric acid or the like at about 50°-250° C. neat or in inertsolvents such as toluene or xylenes gives the ring-closedthieno[3,4-b]pyranone derivative (24). Using reaction conditionsessentially as those described for Scheme 1, reduction of the ketonegives the alcohol 25 which is dehydrated to give the olefin 26.Treatment of the olefin (26) with N-bromosuccinimide and water in polarsolvents gives the bromohydrin 27 which is converted to the epoxide 28.Reaction of 28 with the anions of various amines and amides gives theaminoalcohols 29 (R₁ R₂ =H). Reaction of these derivatives withelectrophiles such as bromine, chlorine, sulfuryl chloride or nitricacid gives the substituted derivatives 29 (R₁ or R₂ =Br, Cl, NO₂),respectively. When the electrophile is an acylating agent such as acetylchloride or acetic anhydride and Lewis or protic acid catalysis isemployed, the product is the acetyl acetoxy derivative 30 (R₁ or R₂=acetyl) which may be converted to the aminoalcohol 29 (R₁ or R₂=acetyl) by treatment with alcoholic base. ##STR10##

Those compounds wherein R₇,R₈ =cycloalkyl can be prepared by reacting acyclic ketone with a Wittig phosphonium ylide reagent to form the3,3-cycloalkylidine carboxylic acid which is the acrylic acid componentof the starting material used to prepare those compounds wherein R₇₁,R₈=cycloalkyl.

Reaction of 29 with bases such as sodium hydride in solvents such asTHF, DMF or the like at 40°-150° C. for 1-16 hours produces enamine 29a.

In a manner analogous to that described for Scheme 1, the epoxide 28 mayalso be reacted with sodium azide in polar solvents to give the azidoalcohol 29 (NR₃ R₄ =N₃). This azide is reduced with reducing agents suchas hydrides or metals in protic acids to give the aminoalcohol 29 (R₃,R₄=H). Reaction of this amine with acylating agents such as acetylchloride, benzoyl chloride or substituted benzoyl chlorides, forexample, gives the compounds of the invention 29 wherein R₃ or R₄ is anacyl group such as acetyl, benzoyl or substituted benzoyl.

Deprotonation of 29 (R₁ R₂ =H) with an agent such as n-butyl lithium,sec-butyl lithium, t-butyl lithium, lithium diisopropylamide or the likein an inert solvent such as THF gives an anion which is reacted withDMF, carbon dioxide or an alkyl chloroformate to give 30 (R₁ R₂ =CHO,CO₂ H, CO₂ R₉ where R₉ =alkyl C₁₋₄). Reaction of 30 (R₁ R₂ =CO₂ H) withthionyl chloride produces 30 (R₁ R₂ =COCl) which is reacted with ammoniaor amines to produce amides 30 (R₁ R₂ =CONH₂ or CONHR₉). Treatment of 30(R₁ R₂ =CONH₂) with dehydratingagents such as trifluoroacetic anhydrideproduces 30 (R₁ R₂ =CN). Treatment of 30 as before with mild basesproduces 29.

Reduction of 9 (Scheme 1, R₁ R₂ =NO₂) by catalytic hydrogenation usingtypical catalysts such as palladium on carbon in the presence of anacylating agent such as acetic anhydride, or benzoyl chloride, forexample, in suitable solvents such as acetic acid, for example, yields 9(R₁ R₂ =NHCR, R=acetyl, benzoyl). In a similar fashion, the reduction of20 (Scheme 2, R₁ R₂ =NO₂) and 29 (Scheme 3, R₁ R₂ =NO₂) yields thecorresponding amide.

The compounds of this invention have antihypertensive activity asdetermined in spontaneously hypertensive rats (SHR). The compounds alsohave effects on potassium ion permeability changes within smooth musclecells as determined in the Rb⁸⁶ efflux assay. [J. M. Smith, A. A.Sanchez and A. W. Jones, Blood Vessels, 1986, 23, 297]

Pharmaceutical compositions containing a compound of the presentinvention as the active ingredient in intimate admixture with apharmaceutical carrier can be prepared according to conventionalpharmaceutical compounding techniques. The carrier may take a widevariety of forms depending on the form of preparation desired foradministration, e.g., intravenous, oral or parenteral. In preparing thecompositions in oral dosage form, any of the usual pharmaceutical mediamay be employed, such as, for example, water, glycols, oils, alcohols,flavoring agents, preservatives, coloring agents and the like in thecase of oral liquid preparations such as, for example, suspensions,elixirs and solutions; or carriers such as starches, sugars, diluents,granulating agents, lubricants, binders, disintegrating agents and thelike in the case of oral solid preparations such as, for example,powders, capsules, and tablets. Because of their ease in administration,tablets and capsules represent the most advantageous oral dosage unitform, in which case solid pharmaceutical carriers are obviouslyemployed. If desired, tablets may be sugar coated or enteric coated bystandard techniques. For parenterals, the carrier will usually comprisesterile water, though other ingredients, for example, to aid solubilityor for preservative purposes, may be included. Injectable suspensionsmay also be prepared, in which case appropriate liquid carriers,suspending agents and the like may be employed. The pharmaceuticalcompositions will generally contain, dosage unit, e.g., tablet, capsule,powder, injection, teaspoonful, aerosol and the like, from about 0.1 toabout 100 mg/kg and preferably from about 0.1 to about 20 mg/kg of theactive ingredient.

The following examples describe the invention in greater particularityand are intended to be a way of illustrating but not limiting theinvention.

BEST MODES OF CARRYING OUT THE INVENTION

Melting point determinations were done on a Thomas Hoover capillarymelting point apparatus and are uncorrected. All compounds had spectra(IR, ¹ H NMR, MS) consistent with their assigned structures and werehomogeneous by thin layer chromatography. ¹ H NMR were determined on aBrucker WP-100 FT or a GE QE-300 spectrometer. MS were determined on aFinnigan Mat 8230 using desorption chemical ionization techniques.Silica Gel 60, 230-400 mesh, was used for both flash chromatography andmedium pressure chromatography.

EXAMPLE 1 3-Methoxy-2-(3-methyl-1-oxo-2-buten-1-yl) thiophene (2)

A solution of 3-methoxythiophene (21.3 g, 0.187 mol) [S. Gronowitz,Arkiv. Kemi., 1958, 12, 239] in dichloromethane (50 mL) was slowly addedto a solution of 3,3-dimethylacryloyl chloride (22 mL, 0.195 mol) andtin(IV) chloride (23 mL, 0.195 mol) in dichloromethane (350 mL) at 0°-5°C. After stirring at 0°-5° C. an additional 1 h, the solution was pouredinto ice water (1 L). The organic layer was separated, washed withwater, and dried over magnesium sulfate. The solvent was evaporated invacuo. The resulting oil was purified by flash chromatography usingdichloromethane as the eluant to give the product, 29.6 g (81%): mp49°-51° C.; IR (KBr): 1671, 1628 and 1430 cm⁻¹ ; MS: m/z 197 (MH⁺); ¹ HNMR (CDCl₃): δ1.98(d, J=1.2 Hz, 3H), 2.23(d, J= 1.1 Hz, 3H), 3.98(s,3H), 6.85(d, J=5.5 Hz, 1H), 6.89(dd, J=1.1 Hz, J=1.2 Hz, 1H) and 7.47(d,J=5.5 Hz, 1H).

Anal. Calcd. for C₁₀ H₁₂ O₂ S: C, 61.20; H, 6.16; S, 16.34. Found: C,61.19; H, 6.17; S, 16.31.

3-Hydroxy-2-(3-methyl-1-oxo-2-buten-1-yl) thiophene (3)

A solution of boron trichloride, (1.0M in dichloromethane, 800 mL, 0.80mol) was slowly added to a solution of3-methoxy-2-(3-methyl-1-oxo-2-buten-1-yl) thiophene (52.3 g, 0.27 mol)in dichloromethane (400 mL) at -10° C. to 5° C. The resultant solutionwas stirred an additional 1.5 h at -5° C. Ice water was added slowlywith rapid stirring. The organic layer was separated, dried over sodiumsulfate, and eluted through a pad of silica gel. The solvent wasevaporated in vacuo and the resultant oil was crystallized from hexanesat -70° C. to give the product, 40.0 g (82%), as a yellow solid: mp32°-33° C.; IR (KBr): 1641, 1581 and 1541 cm⁻¹ ; MS: m/z 183 (MH⁺); ¹ HNMR (CDCl₃): δ2.00(d, J=1.1 Hz, 3H), 2.30(d, J=1.0 Hz, 3H), 6.25(m, 1H),6.75(d, J=5.3 Hz, 1H), 7.37(d, J=5.3 Hz, 1H) and 12.14(s, exchanges withD₂ O, 1H).

Anal. Calcd. for C₉ H₁₀ O₂ S: C, 59.32; H, 5.54; S, 17.59. Found: C,59.35; H, 5.51; S, 17.62.

5,6-Dihydro-5,5-dimethyl-7H-thieno[3,2-b]pyran-7-one (4)

A solution of 3-hydroxy-2-(3-methyl-1-oxo-2-buten-1-yl) thiophene (39.0g, 0.214 mol) and p-toluenesulfonic acid (3.5 g, 18 mmol) in toluene(400 mL) was heated to reflux for 3.5 d. The resultant solution waswashed with saturated aqueous sodium bicarbonate and dried over sodiumsulfate. The solvent was evaporated in vacuo to give a brown oil, 38.62g (99%). A portion of the resultant oil was purified for analysis bydistillation in a Kugelrohr oven at 145° to 155° C. at 0.35 mm Hg togive the product as an amber oil: IR (neat): 2979, 1664, 1530 and 1442cm⁻¹ ; MS: m/z 183 (MH⁺); ¹ H NMR (CDCl₃): δ1.51(s, 6H); 2.67(s, 2H);6.67(d, J=5.4 Hz, 1H) and 7.60(d, J=5.4 Hz, 1H).

Anal. Calcd. for C₉ H₁₀ O₂ S: C, 59.32; H, 5.54; S, 17.69. Found: C,59.39; H, 5.53; S, 17.67.

5,6-Dihydro-7-hydroxy-5,5-dimethyl-7H-thieno[3,2-b]pyran (5)

Sodium borohydride (0.97 g, 25.5 mmol) was added to a solution of5,6-dihydro-5,5-dimethyl-7H-thieno [3,2-b]pyran-7-one (3.1 g, 17.0 mmol)in ethanol (50 mL) and stirred at rt for 2 h. An additional 0.97 g ofsodium borohydride was added and the mixture was stirred 16 h. Themixture was poured into water and extracted with dichloromethane. Thedichloromethane solution was washed with water (5×) and dried overmagnesium sulfate. The solvent was evaporated in vacuo to give theproduct, 2.96 g (95%), as a brown oil: IR (neat): 3373, 2976, 1561 and1400 cm⁻¹ ; MS: m/z 185 (MH⁺ ; ¹ H NMR (CDCl₃): δ1.34(s, 3H), 1.45(s,3H), 1.87(m, 1H), 1.94(d, J=7.0 Hz, 1H, exchanges with D₂ O), 2.16(m,1H), 4.88(m, 1H), 6.57(d, J=5.4 Hz, 1H), 7.13(d, J=5.4 Hz, 1H). This oilwas used without further purification in the next step.

5,5-Dimethyl-5H-thieno[3,2-b]pyran (6, Method A)

A mixture of 5,6-dihydro-7-hydroxy-5,5-dimethyl-7H-thieno [3,2-b]pyran(1.3 g, 7.06 mmol), p-toluenesulfonic acid (0.11 g, 0.58 mmol) andground molecular sieves (1.3 g) was stirred at -5° C. for 1.5 h. Themixture was washed with 1.0N aqueous sodium hydroxide and dried overmagnesium sulfate. The solvent was evaporated in vacuo to give theproduct, 1.17 g (99%), as a red oil: IR (neat): 2976, 1504 and 1531 cm⁻¹; MS: m/z 167 (MH⁺); ¹ H NMR (CDCl₃): δ1.45(s, 6H), 5.27(d, J=9.8 Hz,1H), 6.30 (d, J=9.8 Hz, 1H), 6.60(d, J=5.3 Hz, 1H) and 6.99(d, J=5.3 Hz,1H). This oil was used without further purification in the next step.

5,5-Dimethyl-5H-thieno[3,2-b]pyran (6, Method B)

Sodium borohydride (3.27 g, 86.3 mmol) was added to a solution of5,6-dihydro-5,5-dimethyl-7H-thieno [3,2-b]pyran-7-one (12.1 g, 66.4mmol) in ethanol (100 mL) and the resultant mixture was stirred at rtfor 17 h. The mixture was poured into water (400 mL) and extracted withdichloromethane (2×100 mL). The dichloromethane solution was washed withwater (5×), dried over sodium sulfate, and filtered. Molecular sieves(12 g) and p-toluenesulfonic acid (1.2 g, 6.3 mmol) was added to theresultant solution and stirred at 0° C. for 1.5 h. The reaction mixturewas filtered, washed with saturated aqueous sodium bicarbonate and driedover sodium sulfate. The solvent was evaporated in vacuo to give theproduct, 11.0 g (99%), as a red oil which was identical in all respectsto the product described in Method A.

6-Bromo-7-hydroxy-5,6-dihydro-5,5-dimethyl-7H-thieno[3,2-b]pyran (7)

N-Bromosuccinimide (12.9 g, 72.5 mmol) was added in portions to asolution of 5,5-dimethyl-5H-thieno[3,2-b]pyran (10.95 g, 65.9 mmol) andwater (1.6 mL, 89.5 mmol) in dimethyl sulfoxide (110 mL) at rt. Theresultant solution was stirred at rt for 16 h poured into ice water (400mL) and extracted into dichloromethane. The dichloromethane solution waswashed with water (5×) and dried over sodium sulfate. The solvent wasevaporated in vacuo and the residue was purified by flash chromatographyusing dichloromethane as the eluant to give the product, 11.5 g (66%),as a brown oil: Note that this oil is thermally unstable and decomposeswithin several hours at rt: ¹ H NMR (CDCl₃): δ1.44(s, 3H), 1.60(s, 3H),2.56(d, J=4 Hz, 1H, exchanges with D₂ O), 4.10(d, J=7 Hz, 1H), 4.98(dd,J=4 Hz, J=7 Hz, 1H), 6.56(d, J=5 Hz, 1H), 7.16(d, J=5 Hz, 1H). This oilwas used without further purification in the next step.

5,6-Dihydro-6-hydroxy-5,5-dimethyl-7-(2-oxopyrrolidin-1-yl)-7H-thieno[3,2-b]pyran

Sodium hydride (60% in oil, 1.17 g, 29.3 mmol) was added to a solutionof 6-bromo-7-hydroxy-5,6-dihydro-5,5-dimethyl-7H-thieno[3,2-b]pyran (7.0g, 26.6 mmol) in N,N-dimethylformamide (115 mL) at 0° C. The resultantmixture was stirred at rt for 2 h. 2-Pyrrolidinone (6.1 mL, 79.8 mmol)was added to the solution followed by sodium hydride (60% in oil, 1.17g, 29.3 mmol) and stirring was continued at rt for 4 days. The solutionwas poured into ice water (500 mL) and extracted with dichloromethane.The dichloromethane solution was washed with water (5×) and dried oversodium sulfate. The solvent was evaporated in vacuo and the resultantsolid was triturated in diethyl ether to give the product, 3.91 g (55%),as a colorless solid: mp 154°-155° C.; IR (KBr): 3263, 1665 and 1562cm⁻¹ ; MS: m/z 268 MH⁺); ¹ H NMR (CDCl₃): δ1.30(s, 3H), 1.50(s, 3H),2.07(m, 2H), 2.52(m, 2H), 3.00(d, J=5.5 Hz, 1H, exchanges with D₂ O),3.35(m, 2H), 3.78(dd, J=5.5 Hz, J=9.0 Hz 1H, simplifies to d, J=9.0 Hz,with D₂ O), 5.28(d, J=9.0 Hz, 1H), 6.57(d, 5.4 Hz, 1H) and 7.11(d, J=5.4Hz, 1H).

Anal. Calcd. for C₁₃ H₁₇ NO₃ S: C, 58.40; H, 6.41; N, 5.24; S, 11.99.Found: C, 58.57; H, 6.47; N, 5.23; S, 12.03.

EXAMPLE 25,6-Dihydro-6-hydroxy-5,5-dimethyl-7-(2-oxopiperidin-1-yl)-7H-thieno[3,2-b]pyran

6-Bromo-7-hydroxy-5,6-dihydro-5,5-dimethyl-7H-thieno[3,2-b]pyran (1.5 g,5.7 mmol) and δ-valerolactam (1.7 g, 17.1 mmol) were treated with sodiumhydride (0.50 g, 12.5 mmol) in N,N-dimethylformamide (25 mL) using theprocedure described in Example 1 to give the product as a colorlesssolid, 0.681 g (43%): mp 151°-152° C.; IR (KBr): 3195, 1610 and 1563cm⁻¹ ; MS: m/z 282 (MH⁺); ¹ H NMR (CDCl₃): δ1.29(s, 3H), 1.49(s, 3H),1.81(m, 4H), 2.53(t, J=6.5 Hz, 2H), 3.15(m, 1H), 3.24(m, 1H), 3.68(d,J=5.0 Hz, 1H, exchanges with D₂ O), 3.79(dd, J=5.0 Hz, J=9.1 Hz, 1H,simplifies to d, J=9.1 Hz with D.sub. 2 O), 5.84(d, J=9.1 Hz, 1H),6.57(d, J=5.4 Hz, 1H) and 7.11(d, J=5.4 Hz, 1H).

Anal. Calcd. for C₁₄ H₁₉ NO₃ S: C, 59.76; H, 6.81; N, 4.98; S, 11.40.Found: C, 59.85; H, 7.05; N, 5.11; S, 11.26.

EXAMPLE 35,6-Dihydro-6-hydroxy-5,5-dimethyl-7-(4-nitrobenzamido)-7H-thieno[3,2-b]pyran

6-Bromo-7-hydroxy-5,6-dihydro-5,5-dimethyl-7H-thieno[3,2-b]-pyran (6.8g, 25.8 mmol) and 4-nitrobenzamide (10.7 g, 64.5 mmol) were treated withsodium hydride 60% in oil (2.26 g, 56.8 mmol) in N,N-dimethylformamide(110 mL) using the procedure described for the preparation of5,6-dihydro-6-hydroxy-5,5-dimethyl-7-(2-oxopyrrolidin-1-yl)-7H-thieno[3,2-b]pyran.The reaction mixture was poured into water and extracted into 10%isopropanol in dichloromethane. The solvent was evaporated in vacuo andthe residue was purified by medium pressure chromatography using 2%methanol in dichloromethane as the eluant to give the product, 4.5 g(50%), as a pale yellow solid: mp 183°-186° C. dec; IR (KBr): 3398,1664, 1644 and 1601 cm⁻¹ ; MS: m/z 349 (MH⁺); ¹ H NMR (CDCl₃): δ1.35(s,3H), 1.50(s, 3H), 3.79(d, J=7.9 Hz, 1H), 4.26(bs, 1H, exchanges with D₂O), 5.19(d, d, J=7.9 Hz, and J=7.0 Hz, 1H), 6.59(bd, J=7.0 Hz, 1H,shifts to 6.66 with D₂ O), 6.63(d, J=5.4 Hz, 1H), 7.18(d, J=5.4 Hz, 1H),7.97(d, J=8.8 Hz, 2H) and 8.32(d, J=8.8 Hz, 2H).

Anal. Calcd. for C₁₆ H₁₆ N₂ O₅ S: C, 55.16; H, 4.63; N, 8.04; S, 9.20.Found: C, 55.45; H, 4.76; N, 8.25; S, 9.14.

EXAMPLE 42-Bromo-5,6-dihydro-6-hydroxy-5,5-dimethyl-7-(2-oxopyrrolidin-1-yl)-7H-thieno[3,2-b]pyran

A solution of bromine (0.20 mL, 3.92 mmol) in dichloromethane (5 mL) wasslowly added to a solution of5,6-dihydro-6-hydroxy-5,5-dimethyl-7-(2-oxopyrrolidin-1-yl)-7H-thieno[3,2-b]pyran(1.0 g, 3.74 mmol) at -5° C. The resultant mixture was stirred at rt for2 h. The resulting precipitate was collected by filtration and purifiedby medium pressure chromatography using 5% methanol in dichloromethaneas the eluant to give the product as a colorless solid, 0.28 g (22%): mp162°-165° C.; IR (KBr): 3287, 1666 and 1570 cm⁻¹ ; MS: m/z 346 (MH⁺); ¹H NMR (CDCl₃): δ1.30(s, 3H), 1.47(s, 3H), 2.06(m, 2H), 7.50(m, 2H),3.23(bs, 1H, exchanges with D₂ O), 3.34(m, 2H), 3.76(d, J=9.1 Hz, 1H)5.16(d, J=9.1 Hz, 1H) and 6.56(s, 1H).

Anal. Calcd. for C₁₃ H₁₆ BrNO₃ S: C, 45.10; H, 4.66; N, 4.05. Found: C,45.10; H, 4.40; N, 3.97.

EXAMPLE 55,6-Dihydro-6-hydroxy-5,5-dimethyl-2-nitro-7-(2-oxopyrrolidin-1-yl)-7H-thieno[3,2-b]pyran

Nitric acid (90%, 1.2 mL, 26.9 mmol) was added to a solution of5,6-dihydro-6-hydroxy-5,5-dimethyl-7-(2-oxopyrrolidin-1-yl)-7H-thieno[3,2-b]pyran(1.0 g, 3.74 mmol) in acetic acid (30 mL) at 18° C., and stirred at rtfor 1.5 h. The resultant solution was poured into ice water (200 mL).Within 10 min a yellow solid crystallized which was collected byfiltration, washed with water and triturated in diethyl ether to givethe product, 0.487 g (42%), as a yellow solid: mp 214°-217° C.; IR(KBr): 3216, 1655 and 1512 cm⁻¹ ; MS: m/z 313 (MH⁺); ¹ H NMR (DMSO-d₆):δ1.23(s, 3H), 1.43(s, 3H), 2.00(m, 2H), 2.36(m, 2H), 3.16(m, 1H),3.20(m, 1H), 3.80(d, J=9.5 Hz, 1H), 4.98(d, J=9.5 Hz, 1H), 5.92(bs, 1H,exchanges with D₂ O) and 7.75(s, 1H).

Anal. Calcd. for C₁₃ H₁₆ N₂ O₅ S: C, 49.99; H, 5.16; N, 8.97; S, 10.27.Found: C, 49.70; H, 5.00; N, 8.65; S, 10.33.

EXAMPLE 66-Acetoxy-2-acetyl-5,6-dihydro-5,5-dimethyl-5-(2-oxopyrrolid-1-yl)-7H-thieno[3,2-b]]pyran

A solution of5,6-dihydro-6-hydroxy-5,5-dimethyl-7-(2-oxopyrrolidin-1-yl)-7H-thieno[3,2-b]pyran(1.76 g, 6.58 mmol) and perchloric acid (70%, 10 drops) in aceticanhydride (15mL) was stirred at 60° C. for 2 h. The resultant brownsolution was poured into ice water (100 mL) and the product wasextracted into dichloromethane, washed with water (4×) and dried oversodium sulfate. The solvent was evaporated in vacuo and the resultantoil was purified by medium pressure chromatography using 1% methanol indichloromethane as the eluant to give the product, 0.85 g (37%): mp170°-172° C.; IR (KBr): 1755, 1690, 1666 and 1564 cm⁻¹ ; MS: m/z 352(MH⁺); ¹ H NMR (CDCl₃): δ1.38(s, 3H), 1.39(s, 3H), 1.98(m, 2H), 2.10(s,3H), 2.37(m, 2H), 2.49(s, 3H), 3.23(m, 1H), 3.38(m 1H), 5.14(d, J=9.3Hz, 1H), 5.47(d, J=9.3 Hz, 1H) and 7.16(s, 1H).

Anal. Calcd. for C₁₇ H₂₁ NO₅ S: C, 58.10; H; 6.02; N, 3.99; S, 9.12.Found: C, 57.76; H, 5.87; N, 3.69; S, 9.11.

EXAMPLE 72-Acetyl-5,6-dihydro-6-hydroxy-5,5-dimethyl-7-(2-oxopyrrolidin-1-yl)-7H-thieno[3,2-b]pyran

Aqueous sodium hydroxide (50%, 0.15 g, 1.87 mmol) was added to asolution of6-acetoxy-2-acetyl-5,6-dihydro-5,5-dimethyl-7-(2-oxopyrrolidin-1-yl)-7H-thieno[3,2-b]pyran(0.45 g, 1.28 mmol) in methanol (20 mL) and stirred at rt for 1 h. Thesolution was poured into water (100 mL) and extracted intodichloromethane. The dichloromethane solution was washed with water (3×)and dried over magnesium sulfate. The solvent was evaporated in vacuoand the resultant oil was crystallized from diethyl ether and hexanes togive the product, 0.327 g (83%), as a colorless solid: mp 102°-106° C.;IR (KBr): 1665 and 1561 cm⁻¹ ; MS: m/z 310 (MH⁺); ¹ H NMR (CDCl₃):δ1.31(s, 3H), 1.51(s, 3H), 2.07(m, 2H), 2.48(s, 3H), 2.51(m, 2H),3.34(m, 2H), 3.45(d, J=6.2 Hz, 1H, exchanges with D₂ O), 3.80(dd, J=6.2Hz and J=9.4 Hz, 1H, simplifies to d, J=9.4 Hz, with D₂ O), 5.29(d,J=9.4 Hz, 1H) and 7.14(s, 1H).

Anal. Calcd. for C₁₅ H₁₉ NO₄ S: C, 58.23; H, 6.19; N, 4.53. Found: C,58.30; H, 6.31; N, 4.45.

EXAMPLE 8Acetoxy-5,6-dihydro-5,5-dimethyl-7-(2-oxopyrrolidin-1-yl)-7H-thieno[3,2-b]pyran

A solution of5,6-dihydro-6-hydroxy-5,5-dimethyl-7-(2-oxopyrrolidin-1-yl)-7H-thieno[3,2-b]pyran(2.0 g, 7.48 mmol) and perchloric acid (70%, 10 drops) in aceticanhydride (20 mL) were stirred for 1 h at 0°-5° C. The solution waspoured into ice water (100 mL). The product was extracted intodichloromethane, washed with water (4×), and evaporated in vacuo. Theresultant oil was purified by flash chromatography, using 1% methanol indichloromethane as the eluant, then crystallized from hexanes to givethe product, 2.12 g (92%), as a colorless solid: mp 92°-93° C.; IR(KBr): 1745 and 1684 cm⁻¹ ; MS: 310 (MH⁺); ¹ H NMR (CDCl₃): δ1.37(s,3H), 1.38(s, 3H), 1.98(m, 2H), 2.10(s, 3H), 2.37(m, 2H), 3.24(m, 1 H),3.40(m, 1H), 5.15(d, J=9.1 Hz, 1H), 5.44(d, J=9.1 Hz, 1H), 6.58(d, J=5.4Hz, 1H) and 7.13(d, J=5.4 Hz, 1H).

Anal. Calcd. for C₁₅ H₁₉ NO₄ S: C, 58.23; H, 6.19; N, 4.52; S, 10.36.Found: C, 58.11; H, 5.89; N, 4.31; S, 10.41.

EXAMPLE 95,6-Dihydro-6-hydroxy-5,5-dimethyl-2-nitro-7-(4-nitrobenzamido)-7H-thieno[3,2-b]pyran

5,6-Dihydro-6-hydroxy-5,5-dimethyl-7-(4-nitrobenzamido)-7H-thieno[3,2-b]pyran(1.5 g, 4.30 mmol) was treated with 90% nitric acid (2.5 mL, 53.5 mmol)in acetic acid (25 mL) and stirred at 15°-20° C. for 0.5 h. Theresultant solution was poured into ice water 100 mL and extracted with10% isopropanol in dichloromethane. The dichloromethane solution waswashed with saturated aqueous sodium bicarbonate and dried overmagnesium sulfate. The solvent was evaporated in vacuo and the residuewas purified by medium pressure chromatography using 2% methanol indichloromethane as the eluant, to give the product, 0.489 g (29%), as ayellow solid: mp 221°-225° C. dec; IR (KBr): 3345, 1647 and 1602 cm⁻¹ ;MS: m/z 394 (MH⁺); ¹ H NMR (DMSO-d₆): δ1.26(s, 3H), 1.45(s, 3H),3.90(dd, J=8.8 Hz and J=5.9 Hz, 1H, simplifies to d, J=8.8 Hz with D₂O), 4.98(dd, J=7.6 Hz and J=8.8 Hz, 1H, simplifies to d, J=8.8 Hz withD₂ O), 6.01(d, J=5.9 Hz, 1H exchanges with D₂ O), 7.75(s, 1H), 8.14(d,J=8.8 Hz, 2H) 8.37(d, J=8.8 Hz, 2H) and 9.38(d, J=7.6 Hz, 1H, exchangeswith D₂ O).

Anal. Calcd. for C₁₆ H₁₅ N₃ O₇ S: C, 48.85; H, 3.84; N, 10.68. Found: C,48.91; H, 3.62; N, 10.46.

EXAMPLE 105,6-Dihydro-6-hydroxy-5,5-dimethyl-2-nitro-7-(2-oxopiperidin-1-yl)-7H-thieno[3,2-b]pyran

The title compound was prepared as described in Example 5 starting with5,6-dihydro-6-hydroxy-5,5-dimethyl-7-(2-oxopiperidin-1-yl)-7H-thieno[3,2-b]pyran(1.5 g, 5.33 mmol) and 90% nitric acid (2.5 mL) in acetic acid (25 mL)to give the product, 0.837 g (48%), as a yellow solid: mp 210°-211° C.;IR (KBr): 3231, 1613, 1515 and 1492 cm⁻¹ ; MS: m/z 327 (MH⁺); ¹ H NMR(CDCl₃): δ1.32(s, 3H), 1.51(s, 3H), 1.84(m, 4H), 2.55(m, 2H), 3.20(m,2H), 3.84(d, J=9.5 Hz, 1H), 4.78(bs, 1H, exchanges with D₂ O), 5.86(d,J=9.5 Hz, 1H) and 7.40(s, 1H).

Anal. Calcd. for C₁₄ H₁₈ N₂ O₅ S: C, 51.52; H, 5.56; N, 8.58; S, 9.86.Found: C, 51.26; H, 5.25; N, 8.32; S, 9.86.

EXAMPLE 112-Bromo-5,6-dihydro-6-hydroxy-5,5-dimethyl-7-(2-oxopiperidin-1-yl)-7H-thieno[3,2-b]pyran

The title compound was prepared as described in Example 4 starting with5,6-dihydro-6-hydroxy-5,5-dimethyl-7-(2-oxopiperidin-1-yl)-7H-thieno[3,2-b]pyran(1.4 g, 5.0 mmol) and bromine (0.27 mL, 5.2 mmol) in dichloromethane (30mL). Purification by flash chromatography using 1% methanol indichloromethane as the eluant and recrystallization fromdichloromethane/hexanes gave the product, 3.87 g (78%), as a colorlesssolid: mp 200°-202° C.; IR (KBr): 3442, 2942, 1616, 1571 and 1488 cm⁻¹ ;MS: m/z 360 (MH⁺); ¹ H NMR (CDCl₃): δ1.29(s, 3H), 1.46(s, 3H), 1.82(m,4H), 2.51(m, 2H), 3.12(m, 1H), 3.27(m, 1H), 3.46(d, J=5.0 Hz, 1H,exchanges with D₂ O), 3.78(d, d, J=9.0 Hz, J=5.0 Hz, 1H, simplifies tod, J=9.0 Hz, with D₂ O), 5.74(d, J=9.0 Hz, 1H) and 7.58(s, 1H).

Anal. Calcd. for C₁₄ H₁₈ BrNO₃ S: C, 46.67; H, 5.04; N, 3.89. Found: C,46.99; H, 5.05; N, 3.84.

EXAMPLE 126-Acetoxy-2-acetyl-5,6-dihydro-5,5-dimethyl-7-(4-nitrobenzamido)-7H-thieno[3,2-b]pyran

The title compound was prepared as described in Example 6 starting with5,6-dihydro-6-hydroxy-5,5-dimethyl-7-(4-nitrobenzamido)-7H-thieno[3,2-b]pyran(1.5 g, 4.31 mmol), acetic anhydride (15 mL) and perchloric acid (70%,10 drops) to give the product, 0.86 g (46%), as a pale yellow solid: mp251°-253° C. dec; IR (KBr): 1753, 1670, 1655 and 1530 cm⁻¹ ; MS: m/z 433(MH⁺); ¹ H NMR (CDCl₃): δ1.41(s, 3H), 1.44(s, 3H), 2.14(s, 3H), 2.48(s,3H), 5.18(d, J=9.3 Hz, 1H), 5.40(d, d, J=8.3 Hz, J=9.3 Hz, 1H), 6.83(d,J=8.3 Hz, 1H, shifts to d 6.91 with D₂ O), 7.14(s, 1H); 7.94(d, J=7.1Hz, 2H), 8.30(d, J=7.1 Hz, 2H).

Anal. Calcd. for C₂₀ H₂₀ N₂ O₇ S: C, 55.55; H, 4.66; N, 6.48; S, 7.41.Found: C, 55.34; H, 4.69; N, 6.44; S, 7.31.

EXAMPLE 132-Acetyl-5,6-dihydro-6-hydroxy-5,5-dimethyl-7-(4-nitrobenzamido)-7H-thieno[3,2-b]pyran

6-Acetoxy-2-acetyl-5,6-dihydro-5,5-dimethyl-7-(4-nitrobenzamido)-7H-thienopyran(0.60 g, 1.39 mmol) was treated with aqueous sodium hydroxide (1N, 1.5mL, 1.5 mmol) in methanol (10 mL) at rt and stirred for 2 h. Theresultant solution was poured into water and extracted with 5%isopropanol in dichloromethane. The organic phase was washed with water(3×) and dried over magnesium sulfate. The solvent was evaporated invacuo and the resultant solid triturated in diethyl ether to give theproduct, 0.36 g (66%), as a pale yellow solid: mp 223°-225° C.; IR(KBr): 1647, 1601, 1530 and 1458 cm⁻¹ ; MS: m/z 391 (MH⁺); ¹ H NMR(DMSO-d₆): δ1.23(s, 3H), 1.42(s, 3H), 2.45(s, 3H), 3.84(m, 1H,simplifies to d, J=8.9 Hz with D₂ O), 5.01(m, 1H, simplifies to d, J=8.9Hz, with D₂ O), 5.86(d, J=5.9 Hz, 1H, exchanges with D₂ O), 7.47(s, 1H),8.14(d, J=8.8 Hz, 2H), 8.36(d, J=8.8 Hz, 2H) and 9.27(d, 1H, exchangeswith D₂ O).

Anal. Calcd. for C₁₈ H₁₈ N₂ O₆ S: C, 55.38; H, 4.65; N, 7.18; S, 8.21.Found: C, 55.12; H, 4.63; N, 6.93; S, 8.11.

EXAMPLE 147-(4-Chlorobenzamido)-5,6-dihydro-6-hydroxy-5,5-dimethyl-7H-thieno[3,2-b]pyran

The title compound was prepared as described in Example 3 starting with6-bromo-7-hydroxy-5,6-dihydro-5,5-dimethyl-7H-thieno[3,2-b]pyran (4.75g, 18.1 mmol) and 4-chlorobenzamide (7.0 g, 45 mmol) inN,N-dimethylformamide (125 mL) to give 1.41 (23%) as a yellow solid: mp196°-197° C.; IR (KBr): 3483, 3317, 1632 and 1525 cm⁻¹ ; MS: m/z 338(MH⁺); ¹ H NMR (DMSO-d₆): δ1.20(s, 3H), 1.39(s, 3H), 3.79(m, 1H,simplifies to d, J=8.8 Hz, with D₂ O), 4.98(m, 1H, simplifies to d,J=8.8 Hz with D₂ O), 5.64(d, J=6.0 Hz, 1H, exchanges with D₂ O), 6.58(d,J=5.3 Hz, 1H), 7.29(d, J=5.3 Hz, 1H), 7.56(d, J=6.8 Hz, 2H), 7.93(d,J=6.8 Hz, 2H) and 8.88(d, J=8.3 Hz, 1H, exchanges with D₂ O).

Anal. Calcd. for C₁₆ H₁₆ ClNO₃ S: C, 56.89; H, 4.77; N, 4.15. Found: C,56.72; H, 4.68; N, 4.00.

EXAMPLE 157-(4-Chlorobenzamido)-5,6-dihydro-6-hydroxy-5,5-dimethyl-2-nitro-7H-thieno[3,2-b]pyran

The title compound was prepared as described in Example 9 starting with7-(4-chlorobenzamido)-5,6-dihydro-6-hydroxy-5,5-dimethyl-7H-thieno[3,2-b]pyran(1.23 g, 3.64 mmol) and 90% nitric acid (1.5 mL) in acetic acid (20 mL)to give the product, 0.384 g (28%), as a yellow solid: mp 226°-229° C.dec; IR (KBr): 3315, 1655, 1535 and 1503 cm⁻¹ ; MS: m/z 383 (MH⁺); ¹ HNMR (DMSO-d₆): δ1.25(s, 3H), 1.44(s, 3H), 3.90(m, 1H, simplifies to d,J=8.9 Hz with D₂ O), 4.95(m, 1H, simplifies to d, J=8.9 Hz, with D₂ O),5.94(d, J=6.0 Hz, 1H exchanges with D₂ O), 7.60(d, J=8.6 Hz, 2H),7.72(s, 1H), 7.94(d, J=8.6 Hz, 2H) and 9.11(d, J=7.6 Hz, 1H, exchangeswith D₂ O).

Anal. Calcd. for C₁₆ H₁₅ ClN₂ O₅ S: C, 50.20; H, 3.94; N, 7.32; Cl,9.61; S, 8.69. Found: C, 50.34; H, 3.75; N, 7.00; Cl, 9.36; S, 8.74.

EXAMPLE 165,6-Dihydro-6-hydroxy-5,5-dimethyl-7-(4-trifluoromethylbenzamido)-7H-thieno[3,2-b]pyran

The title compound was prepared as described in Example 3 starting with6-bromo-7-hydroxy-5,6-dihydro-5,5-dimethyl-7H-thieno[3,2-b]pyran (4.5 g,17.1 mmol) and 4-trifluoromethylbenzamide (7.43 g, 39.3 mmol) inN,N-dimethylformamide (75 mL) to give the product, 1.96 g (31%), as acolorless solid: mp 162°-163° C.; IR (KBr): 3396, 1664, 1534 and 1507cm⁻¹ ; MS: m/z 372 (MH⁺); ¹ H NMR (DMSO-d₆): δ1.21(s, 3H), 1.40(s, 3H),3.80(m, 1H, simplifies to d, J=8.7 Hz, with D₂ O), 5.01(m, 1H,simplifies to d, J=8.7 Hz, with D₂ O), 5.68(d, J=6.0 Hz, 1H, exchangeswith D₂ O), 6.59(d, J 5.7 Hz, 1H), 7.31(d, J=5.7 Hz, 1H), 7.88(d, J=8.3Hz, 2H), 8.11(d, J=8.3 Hz, 2H) and 9.05(d, J=8.4 Hz, 1H exchanges withD₂ O).

Anal. Calcd. for C₁₇ H₁₆ F₃ NO₃ S: C, 54.98; H, 4.34; N, 3.77. Found: C,55.01; H, 4.28; N, 3.70.

EXAMPLE 175,6-Dihydro-6-hydroxy-2-nitro-7-(4-trifluoromethylbenzamido)-7H-thieno[3,2-b]pyran

The title compound was prepared as described in Example 9 starting with5,6-dihydro-6-hydroxy-7-(4-trifluoromethylbenzamido)-7H-thieno[3,2-b]pyran(1.5 g, 4.04 mmol) and 90% nitric acid (2.5 mL) in acetic acid (20 mL)to give a yellow solid, 0.165 g (10%): mp 219°-220° C.; IR (KBr): 3310,1661, 1538 and 1504 cm⁻¹ ; MS: m/z 417 (MH⁺); ¹ H NMR (DMSO-d₆):δ1.26(s, 3H), 1.45(s, 3H), 3.92(m, 1H, simplifies to d, J=8.9 Hz, withD₂ O), 4.98(m, 1H, simplifies to d, J=8.9 Hz, with D₂ O), 5.99(d, 1H,exchanges with D₂ O), 7.74(s, 1H), 7.92(d, J=8.5 Hz, 2H), 8.12(d, J=8.5Hz, 2H) and 9.30 (d, 1H, exchanges with D₂ O).

Anal. Calcd. for C₁₇ H₁₅ F₃ N₂ O₅ S: C, 49.03; H, 3.63; N, 6.73. Found:C, 49.01; H, 3.27; N, 6.60.

EXAMPLE 185,6-Dihydro-6-hydroxy-5,5-dimethyl-7-pyrrolidin-1-yl-7H-thieno[3,2-b]pyran

Sodium hydride (60% in mineral oil, 0.145 g, 3.64 mmol) was added to asolution of 6-bromo-5,6-dihydro-7-hydroxy-7H-thieno[3,2-b]pyran (0.87 g,3.31 mmol) in N,N-dimethylformamide (30 mL) at 5° C. The resultantsolution was stirred at rt for 1.5 h. Pyrrolidine (0.91 mL, 10.9 mmol)was added to the solution and stirred at rt for 17 h. The solution waspoured into ice water, and the product was extracted into diethyl ether,washed several times with water and saturated aqueous sodium chloride,and dried over magnesium sulfate. The solvent was evaporated in vacuoand the residue was purified by flash chromatography using 5% methanolin dichloromethane as the eluant to give the product, 0.55 g (66%), as ayellow solid: mp 85°-89° C.; IR (KBr): 3540, 2970, 2965, 1551 and 1394cm⁻¹ ; MS: m/z 254 (MH⁺); ¹ H NMR (CDCl₃): δ1.22(s, 3H), 1.50(s, 3H),1.83(m, 4H), 2.85(m, 4H), 3.27(bs, 1H, exchanges with D₂ O), 3.62(d,J=9.3 Hz, 1H), 3.90(d, J=9.3 Hz, 1H), 6.59(d, J=5.4 Hz, 1H) and 7.03(d,J=5.4 Hz, 1H).

Anal. Calcd. for C₁₃ H₁₉ NO₂ S: C, 61.63; H, 7.56; N, 5.53; S, 12.66.Found: C, 61.38; H, 7.60; N, 5.48; S, 12.58.

EXAMPLE 196-Hydroxy-5,5-dimethyl-7-(2-oxohexamethyleneimin-1-yl)-7H-thieno[3,2-b]pyran

The title compound was prepared as described for Example 3 starting withthe bromoalcohol (2.5 g, 9.5 mmol) and caprolactam (2.1 g, 19.0 mmol) togive 1.35 g (48%): mp 153°-154° C.; IR (KBr): 3200, 1615, 1523 cm⁻¹ ;MS: m/z 296 (MH⁺); ¹ H NMR (CDCl₃): δ7.13(d, J=5.4 Hz, 1H), 6.58(d,J=5.4 Hz, 1H), 5.75(d, J=9.2 Hz, 1H), 3.69(m, 1H), 3.36(d, J=4.9 Hz,1H), 3.23(m, 2H), 2.64(m, 2H), 1.86(m, 6H), 1.47(s, 3H), 1.29(s, 3H).

Anal. Calcd. for C₁₅ H₂₁ NO₃ S: C, 60.99; H, 7.17; N, 4.74; S, 10.85.Found: C, 60.76; H, 6.93; N, 4.76; S, 10.66.

EXAMPLE 206-Hydroxy-5,5-dimethyl-2-nitro-7-(2-oxohexamethyleneimin-1-yl)thieno[3,2-b]pyran

The title compound was prepared as described for Example 5 starting with6-hydroxy-5,5-dimethyl-7-(2-oxohexamethyleneimin-1-yl)thieno[3,2-b]pyran(0.5 g, 1.7 mmol) and nitric acid (90%, 0.55 mL, 12.3 mmol) in aceticacid (15 mL) to give 410 mg (71%): mp 218°-219° C.; IR (KBr): 3340,1627, 1503 cm⁻¹ ; MS: m/z 341 (MH⁺); ¹ H NMR (CDCl₃): δ7.40(s, 1H),5.80(bd, 1H), 3.73(d, J=9.5 Hz, 1H), 3.28(m, 4H), 2.66(m, 2H), 1.87(m,4H), 1.50(s, 3H), 1.32(s, 3H).

Anal. Calcd. for C₁₅ H₂₀ N₂ O₅ S: C, 52.93; H, 5.92; N, 8.23. Found: C,52.71; H, 5.74; N, 7.84.

EXAMPLE 216-Acetoxy-5,5-dimethyl-7-(2-oxohexamethyleneimin-1-yl)thieno-[3,2-b]pyran

The title compound was prepared as described for Example 8 starting with6-hydroxy-5,5-dimethyl-7-(2-oxohexamethyleneiminyl)thieno[3,2-b]pyran(1.5 g, 5.1 mmol) and 70% perchloric acid (10 drops) in acetic anhydride(15 mL) to give 1.5 g (87%): mp 153°-154° C.; IR (KBr): 1668, 1615, 1563cm⁻¹ ; MS: m/z 338 (MH⁺); ¹ H NMR (CDCl₃): δ7.11(d, J=5.3 Hz, 1H),6.57(d, J=5.3 Hz, 1H), 5.99(d, J=9.0 Hz, 1H), 5.10(d, J=9.0 Hz, 1H),3.16(m, 2H), 2.52(m, 2H), 2.09(s, 3H), 1.66(m, 6H), 1.36(s, 3H), 1.34(s,3H).

Anal. Calcd. for C₁₇ H₂₃ NO₄ S: C, 60.51; H, 6.87; N, 4.15. Found: C,60.71; H, 6.54; N, 3.76.

EXAMPLE 226-Hydroxy-5,5-dimethyl-7-(2,5-dioxopiperazin-1-yl)-7H-thieno[3,2-b]pyran

The title compound was prepared as described for Example 3 starting withthe bromoalcohol (2.5 g, 9.5 mmol) and glycine anhydride (2.2 g, 19.0mmol) to give 0.58 g (36%); mp 132°-133° C.; IR (KBr): 3210, 1627, 1510cm⁻¹ ; MS: 297 (MH⁺). ¹ H NMR (CDCl₃): δ7.13(d, J=5.4 Hz, 1H), 6.58(d,J=5.4 Hz, 1H), 5.77(d, J=9.2 Hz, 1H), 3.54(m, 1H), 3.46(d, J=4.9 Hz,1H), 3.23(s, 2H), 2.79(s, 2H), 1.48(s, 3H), 1.31(s, 3H).

Anal. Calcd. for C₁₃ H₁₆ N₂ O₄ S: C, 52.69; H, 5.44; N, 9.45. Found: C,52.53; H, 5.23; N, 9.67.

EXAMPLE 235,6-Dihydro-6-hydroxy-5,5-dimethyl-7-piperidin-1-yl-7H-thieno[3,2-b]pyran

The title compound was prepared as described in Example 18 starting with6-bromo-5,6-dihydro-7-hydroxy-5,5-dimethyl-7H-thieno[3,2-b]pyran (1.5 g,5.7 mmol) and piperidine (1.7 mL, 17.1 mmol) in N,N-dimethylformamide(25 mL) to give an off white solid, 0.977 (64%): mp 68°-70° C.; IR(KBr): 2937, 1549 and 1396 cm⁻¹ ; MS: m/z 162 (MH⁺); ¹ H NMR (CDCl₃):δ1.20(s, 3H), 1.50(s, 3H), 1.52(m, 2H), 1.61(m, 4H), 2.65(m, 2H),2.78(m, 2H), 3.20(bs, 1H, exchanges with D₂ O), 3.55(d, J=9.3 Hz, 1H),3.68(d, J=9.3 Hz, 1H), 6.58(d, J=5.4 Hz, 1H) and 7.04(d, J=5.4 Hz, 1H).

Anal. Calcd. for C₁₄ H₂₁ NO₂ S: C, 62.89; H, 7.92; N, 5.23; S, 11.99.Found: C, 62.86; H, 8.10; N, 5.23; S, 12.12.

EXAMPLE 246-Benzoyloxy-5,6-dihydro-5,5-dimethyl-7-(2-oxopyrrolidin-1-yl)-7H-thieno[3,2-b]pyran

A mixture of5,6-dihydro-6-hydroxy-5,5-dimethyl-7-(2-oxopyrrolidin-1-yl)-7H-thieno[3,2-b]pyran(1.0 g, 3.74 mmol), benzoic anhydride (10 g) and 70% perchloric acid (10drops) were heated to 80° C. for 2 h. The mixture was poured into icewater and extracted with dichloromethane and purified by flashchromatography using 1% methanol in dichloromethane as the eluant. Theproduct was further purified by medium pressure chromatography using thesame eluant, to give the product, 0.893 g (64%), as a grey solid: mp130°-132° C.; IR (KBr): 2981, 1721, 1695 and 1561 cm⁻¹ ; MS: m/z 372(MH⁺); ¹ H NMR (CDCl₃): δ1.43(s, 3H), 1.49(s, 3H), 1.96(m, 2H), 2.23(m,1H), 2.33(m, 1H), 3.31(m, 1H), 3.47(m, 1H), 5.44(d, J=9.3 Hz, 1H),5.64(d, J=9.3 Hz, 1H), 6.62(d, J=5.3 Hz, 1H), 7.15(d, J=5.3 Hz, 1H),7.46(t, J=7.4 Hz, 2H), 7.59(t, J=7.4 Hz, 1H) and 8.03(d, J=7.4 Hz, 2H).

Anal. calcd. for C₂₀ H₂₁ NO₄ S: C, 64.67; H, 5.70; N, 3.77; S, 8.63.Found: C, 64.94; H, 5.57; N, 3.59; S, 8.64.

EXAMPLE 25 6-Hydroxy-5,5-dimethyl-7-(nicotinamido)-7H-thieno[3,2-b]pyran

The title compound was prepared as described for Example 3 starting with6-bromo-5,6-dihydro-7-hydroxy-5,5-dimethyl-7H-thieno[3,2-b]pyran (4.0 g,15.2 mmol) and nicotinamide (3.7 g, 30.4 mmol) to give 1.1 g (24%): m.p.248°-49° C.; IR (KBr): 3329, 3312, 1648, 1594, 1569 cm⁻¹ ; MS: m/z 305(MH⁺); ¹ H NMR (CDCl₃): δ9.02(s, 1H), 8.79(d, J=5.6 Hz, 1H), 8.14(d,J=5.6 Hz, 1H), 7.44(m, 1H), 7.18(d, J=5.4 Hz, 1H), 6.64(d, J=5.4 Hz,1H), 6.55(d, J=5.6, 1H), 5.20(m, 1H), 4.46(brs, 1H), 3.81(d, J=9.4 Hz,1H), 1.50(s, 3H), 1.36(s, 3H).

Anal. Calcd. for C₁₅ H₁₆ N₂ O₃ S: C, 59.19; H, 5.30; N, 9.20. Found: C,58.91; H, 5.10; N, 9.13.

EXAMPLE 266-Hydroxy-7-(2-imidazolidon-1-yl)-5,5-dimethyl-7H-thieno-[3,2-b]pyran

The title compound was prepared as described for Example 3 starting with6-bromo-5,6-dihydro-7-hydroxy-5,5-dimethyl-7H-thieno[3,2-b]pyran (4.0 g,15.2 mmol) and 2-imidazolidone (2.9 g, 30.4 mmol) to give 630 mg (15%):m.p. 156°-58° C.; IR (KBr): 3390, 1698, 1565, 1489 cm⁻¹ ; MS: m/z 309(MH⁺); ¹ H NMR (CDCl₃): δ7.13(d, J=5.4 Hz, 1H), 6.54(d, J=5.4 Hz, 1H),5.15(m, 1H), 4.67(m, 2H), 3.79(d, J=9.4 Hz, 1H), 3.24(m, 2H), 1.48(s,3H), 1.31(s, 3H).

Anal. Calcd. for C₁₂ H₁₆ N₂ O₃ S: C, 53.71; H, 6.01; N, 10.44. Found: C,53.78; H, 6.14; N, 10.42.

EXAMPLE 276-Hydroxy-5,5-dimethyl-7-(isonicotinamido)-7H-thieno[3,2-b]pyran

The title compound was prepared as described for Example 3 starting with6-bromo-5,6-dihydro-7-hydroxy-5,5-dimethyl-7H-thieno[3,2-b]pyran (4.0 g,15.2 mmol) and isonicotinamide (3.7 g, 30.4 mmol) to give 510 mg (11%):m.p. 223°-34° C.; IR (KBr): 3324, 3304, 1649, 1569, 1536 cm⁻¹ ; MS: m/z305 (MH⁺); ¹ H NMR (CDCl₃): δ8.78(d, J=5.8 Hz, 2H), 7.63(d, J=5.8 Hz,2H), 7.18(d, J=5.4 Hz, 1H), 6.63(d, J=5.4 Hz, 1H), 5.19(m, 1H),4.28(brs, 1H), 3.79(d, J=9.4 Hz, 1H), 1.49(s, 3H), 1.35(s, 3H).

Anal. calcd. for C₁₅ H₁₆ N₂ O₃ S: C, 59.19; H, 5.30; N, 9.20. Found: C,58.85; H, 5.07; N, 9.05.

EXAMPLE 285,6-Dihydro-5,5-dimethyl-7-(pyrrolidin-1-yl)-7H-thieno[3,2-b]pyran

A solution of 5,6-dihydro-5,5-dimethylthieno[3,2-b]pyran-7-one (1.0 g,5.5 mmol), pyrrolidine (2.3 ml, 27.4 mmol) sodium cyanoborohydride(0.345 g, 5.5 mmol) and 1N aqueous hydrochloric acid (5.5 ml, 5.5 mmol)in methanol (15 ml) was stirred at rt for 1 day. Additional sodiumcyanoborohydride (0.345 g, 5.5 mmol) was added and the solution wasstirred an additional 1 day; additional sodium cyanoborohydride (1.0 g,15.9 mmol) was added again and the mixture stirred 5 additional days.The mixture was poured into water (100 ml) and extracted withdichloromethane. The dichloromethane solution was washed with water anddried over sodium sulfate. The solvent was evaporated in vacuo and theresidue was purified by medium pressure chromatography using 2% methanolin dichloromethane as the eluant to give the product 0.70 g (54%) as ayellow solid; mp 49°-50° C.; IR (KBr): 2971, 1560 and 1394 cm⁻¹ ; MS:m/z 238 (MH⁺); ¹ H NMR (CDCl₃): δ1.27(s,3H), 1.45(s3H), 1.80(m,4H),1.91(m,2H), 2.76(m,4H), 4.09(m,1H), 6.57(d,J=5.4 Hz,1H), and7.04(d,J=5.4 Hz,1H).

Anal. Calcd. for C₁₃ H₁₉ NOS: C,65.78; H,8.07; N,5.90. Found: C,65.35;H,8.24; N,5.97.

EXAMPLE 297-(4-Cyanobenzamido)-5,6-dihydro-6-hydroxy-5,5-dimethyl-7H-thieno[3,2-b]pyran

The title compound was prepared as described in Example 3 starting with6-bromo-7-hydroxy-5-6-dihydro-5,5-dimethyl-7H-thieno[3,2-b] pyran (6.73g, 25.6 mmol), sodium hydride (2.14 g, 53.8 mmol), 4-cyanobenzamide(12.0 g, 82.1 mmol) and N,N-dimethylformamide (75 ml) to give theproduct, after recrystallization from dichloromethane and hexanes, 0.82g (10%) as a colorless solid; mp 177°-178° C.; IR(KBr): 3420, 1648, 1545and 1496 cm⁻¹ ; MS: m/z 329 (MH⁺); ¹ H NMR (CDCl₃):δ1.35(s,3H),1.50(s,3H),3.79(dd,J=7.8 Hz, J=2.5 Hz, 1H, simplifies to d,J=7.8 Hz with D₂ O), 4.31(d,J=2.5 Hz, 1H, exchanges with D₂ O), 5.17(m,1H), 6.56(bd, J=6.8 Hz, 1H), 6.63(d,J=5.4 Hz, 1H), 7.18(d,J=5.4 Hz, 1H),7.78(d,J=8.2 Hz, 2H) and 7.91(d, J=8.2 Hz,2H).

Anal. Calcd for C₁₇ H₁₆ N₂ O₃ S: C,62.18; H,4.91;N,8.53 S,9.75. Found:C,62.10; H, 4.74; N, 8.21; S,9.56.

EXAMPLE 306-Acetoxy-2-acetyl-7-(4-trifluoromethylbenzamido)-5,6-dihydro-5,5-dimethyl-7H-thieno[3,2-b]pyran

The title compound was prepared as described in Example 6 starting with7-(4-trifluoromethylbenzamido)-5,6-dihydro-6-hydroxy-5,5-dimethyl-7H-thieno[3,2-b]pyran(1.5 g, 4.04 mmol), perchloric acid (70%, 10 drops) and acetic anhydride(20 ml) to give the product after crystallization from dichloromethaneand hexanes 0.382 g (21%) as a colorless solid; mp 225°-227° C.; IR(KBr):1755, 1668, 1654, 1541 and 1471 cm⁻¹ ; MS=m/z 456 (MH⁺);¹ H NMR(CDCl₃): δ1.41(s,3H), 1.43(s,3H), 2.13(s,3H), 2.47(s,3H), 5.17(d,J=9.3Hz,1H), 5.42(m,1H), 6.77(bd,J=7.9 Hz,1H), 7.14(s,1H), 7.72(d,J=8.3 Hz,2H) and 7.88(d,J=8.3 Hz,2H).

Anal. calcd. for C₂₁ H₂₀ F₃ NO₅ S: C,55.42; H,4.43; N,3.08. Found:C,55.06; H, 4.28; N,2.82.

EXAMPLE 312-Acetyl-7-(4-trifluoromethylbenzamido)-5,6-dihydro-6-hydroxy-5,5-dimethyl-7H-thieno[3,2-b]pyran

A mixture of potassium carbonate (92 mg, 0.67 mmol) and6-acetoxy-2-acetyl-7-(4-trifluoromethylbenzamido)-5,6-dihydro-5,5-dimethyl-7H-thieno[3,2-b]pyran(0.30 g, 0.66 mmol) in methanol was stirred at rt for 3 h. The mixturewas poured into ice water and a white solid crystallized within tenminutes. The solid was collected by filtration, washed with water, airdried and recrystallized from dichloromethane and hexanes to give theproduct 0.21 g (77%) as a colorless solid; mp 227°-229° C.; IR (KBr):1652, 1541 and 1414 cm⁻¹ ; MS: m/z 414 (MH⁺); ¹ H NMR (CDCl₃): δ1.364.37(bs,1H exchanges with D₂ O), 5.24(m,1H), 6.61(bd,1H), 7.17(s,1H),7.74(d,J=8.2 Hz,2H) and 7.94(d,J=8.2 Hz,2H).

Anal. calcd. for c₁₉ H₁₈ F₃ NO₄ S: C,55.20; H,4.40; N,3.39. Found: C,55.21; H,4.21; N, 3.29.

EXAMPLE 325,6-Dihydro-6-methoxy-5,5-dimethyl-7-(2-oxopyrrolidin-1-yl)-7H-thieno[3,2-b]pyran

5,6-Dihydro-6-hydroxy-5,5-dimethyl-7-(2-oxopyrrolidin-1-yl)-7H-thieno[3,2-b]pyran(1.1 g, 4.11 mmol) was added to a mixture of sodium hydride (60% inmineral oil, 0.172 g, 4.32 mmol) in N,N-dimethylformamide (20 ml) at 0°C. and stirred for 1.5 h. Methyl iodide (0.28 ml, 4.52 mmol) was addedto the resultant mixture and the mixture stirred at rt for 1 h. Themixture was poured into ice water (100 ml) and extracted withdichloromethane. The dichloromethane solution was washed with water (5×)and dried over magnesium sulfate. The solvent was evaporated in vacuoand the residue was crystallized from dichloromethane and hexanes togive the product 0.825 g (71%) as a colorless solid; mp 117°-118° C.;IR(KBr): 2979, 1677, 1572 and 1420 cm⁻¹ ; MS: m/z 282 (MH⁺); ¹ H NMR(CDCl₃): δ1.27 (s, 3H), 1.48(s,3H), 2.05(m,2H), 2.50(m,2H), 3.33(m,2H),3.41(d,J=8.8 Hz, 1H), 3.51(s,3H), 5.33(d,J=8.8 Hz, 1H), 6.55(d,J=5.4 Hz,1H) and 7.09(d,J=5.4 Hz, 1H).

Anal Calcd. for C₁₄ H₁₉ NO₃ : C,59.76; H,6.81; N,4.98. Found: C,59.73;H,6.46; N,4.81.

EXAMPLE 337-Azido-5,6-dihydro-6-hydroxy-5,5-dimethyl-7H-thieno[3,2-b]pyran

Sodium Hydride (60% in oil, 3.77 g, 94.1 mmol) was added to a solutionof 6-bromo-7-hydroxy-5,6-dihydro-5,5-dimethyl-7H-thieno [3,2-b]pyran(23.6 g, 89.7 mmol) in N,N-dimethyl formamide (275 ml) at 0° C. Themixture was stirred at rt for 1.5 h and sodium azide (17.0 g, 0.269 mol)was added. The resultant mixture was stirred at rt for 3 days, thenpoured into ice water (1200 ml) and extracted with diethyl ether. Theether solution was washed with water (5×) and dried over magnesiumsulfate. The solvent was evaporated in vacuo and the residue waspurified by flash chromatography using 15% hexanes in dichloromethane asthe eluant to give the product 5.1 g (25%) as a tan solid; mp 48°-50°C.; IR (KBr): 3471, 2104, 1568 and 1402 cm⁻¹ ; MS:m/z 226(MH⁺); ¹ H NMR(CDCl₃ ): δ1.31 (s,3H), 1.47(s,3H), 2.29(d,J=5.8 Hz, 1H, exchanges withD₂ O), 3.78(m,1H, simplifies to d, J=7.0 Hz, with D₂ O), 4.44(d,J=7.0Hz, 1H), 6.58(d,J=5.4 Hz, 1H) and 7.18(d,J=5.4 Hz,1H).

Anal. Calcd. for C₉ H₁₁ N₃ O₂ S: C, 47.99; H,4.92; N,18.65. Found:C,48.36; H,4.91; N,18.12.

EXAMPLE 347-Amino-5,6-dihydro-6-hydroxy-5,5-dimethyl-7H-thieno]3,2-b]pyran

7-Azido-5,6-dihydro-6-hydroxy-5,5-dimethyl-7H-thieno[3,2-b]pyran (2.0 g,8.88 mmol) was added carefully in small portions to a mixture of lithiumaluminum hydride (0.67 g, 17.8 mmol) in diethyl ether (40 ml). Theresultant mixture was stirred an additional 1 h at rt and quenched withsuccessive dropwise addition of water (0.7 ml), 15% aqueous sodiumhydroxide (0.7 ml) and water (2.0 ml). The aluminum salts were removedby filtration and the ether solution was dried over magnesium sulfate.The solvent was evaporated in vacuo to give the product 1.64 g (93%) asa beige solid; mp 111°-116° C.; IR(KBr):3110, 2971, 1565 and 1403 cm⁻¹ ;MS:m/z 200 (MH⁺); ¹ H NMR (CDCl₃):δ1.24(s,3H), 1.48(s,3H), 1.85(bs,3H,exchanges with D₂ O), 3.38(d,J=8.6 Hz,1H), 3.70(d,J=8.6 Hz,1H),6.55(d,J=5.4 Hz,1H) and 7.07(d,J=5.4 Hz,1H).

Anal. Calcd. for C₉ H₁₃ NO₂ S: C,54.25; H,6.58; N,7.03; S,1609. Found:C,54.80; H,6.23; N,6.44; S,15.91.

EXAMPLE 357-(4-Fluorobenzamido)-5,6-dihydro-6-hydroxy-5,5-dimethyl-7H-thieno[3,2-b]pyran

A solution of 4-fluorobenzoyl chloride (0.91 ml, 7.72 mmol) indichloromethane (5 ml) was slowly added to a solution of7-amino-5,6-dihydro-6-hydroxy-5,5-dimethyl-7H-thieno[3,2-b]pyran (1.4 g,7.03 mmol) and triethylamine (2.9 ml, 21.1 mmol) in dichloromethane (30ml) at 0° C. The resultant mixture was stirred an additional 1 h at 0°C., then washed with 1N hydrochloric acid, then with saturated aqueoussodium bicarbonate and dried over magnesium sulfate. The solvent wasevaporated in vacuo and the residue was recrystallized fromdichloromethane and hexanes to give the product 1.91 g (85%) as acolorless solid; mp 162°-164° C.; IR (KBr): 3365, 1648, 1604, 1535 and1500 cm⁻¹ ; MS:m/z 322 (MH⁺); ¹ H NMR (CDCl₃):δ1.35(s,3H), 1.50(s,3H),3.76(dd, J=2.0 Hz, J=7.9 Hz, 1H, simplifies to d,J=7.9 Hz, with D₂ O),4.72(d, J=2.0 Hz, 1H, exchanges with D₂ O), 5.14(m,1H), 6.45(bd,1H),6.62(d,J=5.4 Hz, 1H), 7.15(m,3H), and 7.82(m,2H).

Anal Calcd. for C₁₆ H₁₆ FNO₃ S: C, 59.80; H,5.02, N,4.35. Found:C,59.81; H,5.07; N,4.18.

EXAMPLE 367-Benzamido-5,6-dihydro-6-hydroxy-5,5-dimethyl-7H-thieno[3,2-b]pyran

The title compound was prepared as described in Example 34 starting withbenzoyl chloride (0.95 ml), triethylamine (3.3 ml, 23 mmol) and7-amino-5,6-dihydro-6-hydroxy-5,5-dimethyl-7H-thieno[3,2-b]pyran (1.55g, 7.78 mmol) in dichloromethane (35 ml) to give the product 1.07 g(45%) as a colorless solid; mp 219°-220° C.; IR(KBr):3398, 1657, 1526and 1490 cm⁻¹ ; MS:m/z 304 (MH⁺); ¹ H NMR (DMSO-d₆):δ1.21(5,3H),1.39(5,3H), 3.81(m,1H, simplifies to d, J=8.8 Hz, with D₂ O), 5.00(m,1Hsimplifies to d, 5=8.8 Hz, with D₂ O), 5.61(d,J=6.0 Hz, 1H, exchangeswith D₂ O), 6.58(d,J=5.3 Hz,1H), 7.29(d,J=5.3 Hz,1H), 7.47(m,3H),7.92(dd,J=1.3 Hz, J=8.2 Hz,2H) and 8.79(d,J=8.3 Hz, 1H, exchanges withD₂ O).

Anal. Calcd. for C₁₆ H₁₇ NO₃ S: C,63.35; H,5.65; N,4.62; S,10.57. Found:C,63.12; H,5.28; N,4.24; S,10.37.

EXAMPLE 37 Antihypertensive Activity

Antihypertensive activity was assessed using a direct measurement ofmean arterial blood pressure in spontaneously hypertensive rats (SHR).On the day of the experiment, catheters were implanted into the leftcarotid artery and the left jugular vein of SHR under light etheranesthesia. The catheters were exteriorized at the nape of the neck andsecured with an adhesive wrap. Animals were then placed in stainlesssteel restraint cages in a quiet room and allowed at least 90 minpost-surgical recovery before recordings were collected. Recordings ofarterial pressure were obtained using a Statham pressure transducerconnected to a Gould 2800 chart recorder. Groups of 4-6 SHR received asingle oral dose of drug or vehicle (0.5% methylcellulose) administeredby gavage at doses of 0.03 to 20 mg/kg. The percent reduction of meanarterial blood pressure compared to controls is reported.

EXAMPLE 38 Rb⁸⁶ Efflux from Smooth Muscle

Rabbit aorta are removed from freshly sacrificed animals. The vesselsare cleaned and cut into small circular rings. The rings are placed ontostainless steel wires and immersed in a biological buffer (37° C.)bubbled with 95% O₂ /5% CO₂. Rb⁸⁶ (4-5 μCi/mL) is added to 40-50 mLbuffer containing all of the aortic rings. This loads each ring with anapproximately equal amount of Rb⁸⁶. After 3-4 hours, sets of 2 rings areplaced into 4 mL vials of fresh buffer. A background efflux rate isdetermined over a 30-40 minute period. Test compound is then added to anumber of the vials (usually five) as the rings are moved through the 4mL solutions over a set time period (usually 10 minutes). Finally, therings are placed into the vials containing no test compound for a periodof 10-20 minutes. At the completion of the experiment, the tissues aredigested overnight in Prostol before placing into scintillation cocktailto determine the total amount of radioactivity remaining within thetissues. An aliquot is removed from each of the efflux vials andquantitated in a liquid scintillation spectrometer. An efflux rate (or %change from pre-drug rates) is calculated and followed with time in thepresence and absence of test compounds.

The pharmacological activity of the thienopyran derivatives issummarized below. Blood pressure reduction was measured in thespontaneously hypertensive rats (SHR). The Rb⁸⁶ efflux assay is ameasure of potassium ion permeability changes within vascular smoothmuscle cells.

                                      TABLE                                       __________________________________________________________________________    Biological Activity of Thienopyran Derivatives                                EX.                                                                              NR.sub.3 R.sub.4                                                                          R.sub.6                                                                          R.sub.2                                                                          DOSE.sup.a                                                                         SHR.sup.b                                                                         DOSE.sup.c                                                                         %.sup.d                                    __________________________________________________________________________     1 pyrrolidinon-1-yl                                                                         OH H  20 po                                                                              -55%                                                                              100  25%                                         4 pyrrolidinon-1-yl                                                                         OH 2-Br                                                                             20 po                                                                              -43%                                                                              100  90%                                         5 pyrrolidinon-1-yl                                                                         OH 2-NO.sub.2                                                                       20 po                                                                              -60%                                                                              100  114%                                        2 piperidon-1-yl                                                                            OH H  20 po                                                                              -53%                                                                              100  40%                                         8 pyrrolidinon-1-yl                                                                         OAc                                                                              H  20 po                                                                              -10%                                                 6 pyrrolidinon-1-yl                                                                         OAc                                                                              2-Ac                                                                             20 po                                                                              -33%                                                                              100  23%                                         7 pyrrolidinon-1-yl                                                                         OH 2-Ac                                                                             20 po                                                                              -62%                                                                              100  57%                                         9  -p-NO.sub.2 PhCONH                                                                       OH 2-NO.sub.2                                                                       20 po                                                                              -29%                                                                              100  30%                                        17  -p-CF.sub.3 PhCONH                                                                       OH 2-NO.sub.2                                                                       20 po                                                                              -14%                                                12  -p-NO.sub.2 PhCONH                                                                       OAc                                                                              2-Ac                                                                             20 po                                                                              -20%                                                14  -p-ClPhCONH                                                                              OH H                                                           13  -p-NO.sub.2 PhCONH                                                                       OH 2-Ac                                                                             20 po                                                                              -63%                                                                              100  26%                                        15  -p-ClPhCONH                                                                              OH 2-NO.sub.2                                                                       20 po                                                                              -42%                                                                              100  39%                                        19 homopiperidinon-1-yl                                                                      OH H  20 po                                                                              -12%                                                10 piperidon-1-yl                                                                            OH 2-NO.sub.2                                                                       20 po                                                                              -65%                                                24 pyrrolidinon-1-yl                                                                         OBz                                                                              H  20 po                                                                              -12%                                                20 homopiperidinon-1-yl                                                                      OH 2-NO.sub.2                                                                       20 po                                                                              -34%                                                18 pyrrolidin-1-yl                                                                           OH H  100 po                                                                             -48%                                                11 piperidon-1-yl                                                                            OH 2-Br                                                                             20 po                                                                              -64%                                                21 2-oxohexamethylene-                                                                       OAc                                                                              H  20 po                                                                               -9%                                                   imin-1-yl                                                                  31  -p-CF.sub.3 PhCONH                                                                       OH 2-Ac                                                                             20 po                                                                              -26%                                                35  -p-FPhCONH OH H  20 po                                                                               -8%                                                __________________________________________________________________________     .sup.a Dose of test compound in groups of 3-6 spontaneously hypertensive      rats (SHR) administered po, mg/kg                                             .sup.b % Decrease in mean arterial blood pressure compared to pretreatmen     control values                                                                .sup.c Concentration of test compound in μ--M                              .sup.d % Increase of Rb.sup.86 efflux from smooth muscle.                

What is claimed is:
 1. A compound of the formula: ##STR11## X ishydrogen, chloro or bromo; M is keto or hydroxy or M and X together forma double bond; R₁ and R₂ are selected from the group consisting ofhydrogen, nitro, cyano, trifluromethyl, halogen, alkyl (C₁₋₄) acyl(C₂₋₄), substituted acyl (C₂₋₄), alkoxycarbonyl (C₁₋₄), COOH, CONH₂,CHO, benzoyl; and substituted benzoyl; and R₇ and R₈ are hydrogen oralkyl (C₁₋₄) or when taken together form a ring (C₅₋₈).
 2. The compoundof claim 1 wherein ##STR12##
 3. The compound of claim 1 wherein##STR13##
 4. The compound of claim 1 wherein ##STR14##
 5. A compound ofclaim 1 selected from the group consistingof:5,6-dihydro-5,5-dimethyl-7H-thieno[3,2-b]pyran-7-one,5,6-dihydro-7-hydroxy-5,5-dimethyl-7H-thieno[3,2-b]pyran,5,5-dimethyl-5H-thieno[3,2-b]pyran,3,4-dihydro-3,3-dimethyl-5H-thieno[2,3-b] pyran-5-one,3,4-dihydro-5-hydroxy-3,3-dimethyl-5H-thieno[2,3-b]pyran,3,3-dimethyl-3H-thieno[2,3-b]pyran,4,5-dihydro-4,4-dimethyl-4H-thieno[3,4-b]pyran-6-one,4,5-dihydro-6-hydroxy-4,4-dimethyl-6H-thieno[3,4-b]pyran, and4,4-dimethyl-4H-thieno[3,4-b]pyran.